Apoptosis, or programmed cell death, is a principal mechanism by which organisms eliminate unwanted cells. The deregulation of apoptosis, either excessive apoptosis or the failure to undergo it, has been implicated in a number of diseases such as cancer, acute inflammatory and autoimmune disorders, ischemic diseases and certain neurodegenerative disorders [see generally Science, 281, pp. 1283-1312 (1998); and Ellis et al., Ann. Rev. Cell. Biol., 7, p. 663 (1991)].
Caspases are a family of cysteine protease enzymes that are key mediators in the signaling pathways for apoptosis and cell disassembly [N. A. Thornberry, Chem. Biol., 5, pp. R97-R103 (1998)]. These signaling pathways vary depending on cell type and stimulus, but all apoptosis pathways appear to converge at a common effector pathway leading to proteolysis of key proteins. Caspases are involved in both the effector phase of the signaling pathway and further upstream at its initiation. The upstream caspases involved in initiation events become activated and in turn activate other caspases that are involved in the later phases of apoptosis.
The utility of caspase inhibitors to treat a variety of mammalian disease states associated with an increase in cellular apoptosis has been demonstrated using peptidic caspase inhibitors. For example, in rodent models, caspase inhibitors have been shown to reduce infarct size and inhibit cardiomyocyte apoptosis after myocardial infarction, to reduce lesion volume and neurological deficit resulting from stroke, to reduce post-traumatic apoptosis and neurological deficit in traumatic brain injury, to be effective in treating fulminant liver destruction, and to improve survival after endotoxic shock [H. Yaoita et al., Circulation, 97, pp. 276-281 (1998); M. Endres et al., J. Cerebral Blood Flow and Metabolism, 18, pp. 238-247, (1998); Y. Cheng et al., J. Clin. Invest., 101, pp. 1992-1999 (1998); A. G. Yakovlev et al., J. Neurosci., 17, pp. 7415-7424 (1997); I. Rodriquez et al., J. Exp. Med., 184, pp. 2067-2072 (1996); and Grobmyer et al., Mol. Med., 5, p. 585 (1999)]. However, due to their peptidic nature, such inhibitors are typically characterized by undesirable pharmacological properties, such as poor cellular penetration and cellular activity, poor oral absorption, poor stability and rapid metabolism [J. J. Plattner and D. W. Norbeck, in Drug Discovery Technologies, C. R. Clark and W. H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126]. This has hampered their development into effective drugs. These and other studies with peptidic caspase inhibitors have demonstrated that an aspartic acid residue is involved in a key interaction with the caspase enzyme [K. P. Wilson et al., Nature, 370, pp. 270-275 (1994); and Lazebnik et al., Nature, 371, p. 346 (1994)].
Accordingly, peptidyl and non-peptidyl aspartic acid compounds are useful as caspase inhibitors. For examples, WO96/03982 reports azaaspartic acid analogs effective as interleukin-1β converting enzyme (“ICE”) inhibitors.
However, due to their acidic nature such peptidic and non-peptidyl aspartic acid derivatives are charged at physiological pH. This has inhibited their ability to cross the blood brain barrier and to penetrate cells at therapeutically useful levels.
Accordingly, it would be advantageous to have drug derivatives that are targeted at the diseased organs, especially the brain and central nervous system. In addition, it would be advantageous to have drug derivatives that are targeted at the diseased cells rather than at healthy cells, thus reducing undesirable side-effects.
The use of prodrugs imparts desired characteristics such as increased bioavailability or increased site-specificity for known drugs. Various lipids and phospholipids can be used in the preparation of particular types of prodrugs.
WO94/22483 reports cell permeable prodrugs, comprising a pharmacologically active carboxylic acid such as branched-chain aliphatic carboxylic acids (e.g., valproic acid), salicylic acids (e.g., acetylsalicylic acid), steroidal carboxylic acids (e.g., lysergic and isolysergic acids, monoheterocyclic carboxylic acids (e.g., nicotinic acid) and polyheterocyclic carboxylic acids (e.g., penicillins and cephalosporins), covalently linked to an intracellular transporting adjuvant. One such embodiment of the intracellular transporting adjuvant is a lysophospholipid.
WO99/02485 reports compounds of the formula:
wherein R1 is a saturated or unsaturated chain of 1-5 carbons in length; R2 is a saturated or unsaturated chain of 3-10 carbons in length; and A is COOL or CONR′R″, wherein L is a lipid moiety selected from the group consisting of glycerol, C3-20 fatty acid monoglycerides, C3-20 fatty acid diglycerides, hydroxy-C2-6-alkyl esters of C3-20 fatty acids, hydroxy-C2-6-alkyl esters of lysophosphatidic acids, lyso plasmalogens, lysophospholipids, lysophophatidic acid amides, glycerophosphoric acids, sphingolipids, lysophophatidylethanolamine, and N-mono and N,N-di-(C1-4)alkyl derivatives of the amines thereof; and R′ and R″ are each independently selected from the group consisiting of hydrogen and a lower alkyl group comprising 1-5 carbon atoms.
WO00/31083 reports compounds of the formula:
wherein R1 is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain having from 2 to 30 carbon atoms; R2 is H or a phospholipid head group; D is a residue of a non-steroidal anti-inflammatory drug having a functional group selected from the group consisting of carboxyl, hydroxyl, amine and thiol, wherein D is attached through said functional group to a bridging group, —C(O)-Z-X—, wherein Z is a saturated or unsaturated carbon chain having from 2 to 15 atoms, and X is selected from amino, hydroxy, thio and carbonyl groups, such that when the functional group of D is carboxyl, X is selected from amino, hydroxy and thio, and when the functional group of D is amino, hydroxy or thio, X is a carbonyl group.
WO01/19320 reports compounds of the formula:
wherein R1 is a saturated or unsaturated, straight-chain or branched, substituted or unsubstituted hydrocarbon chain having from 2 to 30 carbon atoms; R2 is H or a phospholipid head group; Z is a saturated or unsaturated, straight-chain or branched, substituted or unsubstituted hydrocarbon chain having from 2 to 15 carbon atoms, which may include cyclic elements, and optionally is interrupted by one or more atoms selected from oxygen and sulfur atoms; X is a direct covalent bond or selected from the group consisting of O, S, NH and C(O) groups; and D is a residue of an anti-proliferative drug, wherein the bound anti-proliferative drug residue is an inactive form of the drug which is selectively activated in cells and tissues with elevated phospholipase activity.
WO02/11666 reports compounds of the formula:
or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are the same or different, saturated or unsaturated aliphatic chain comprising from 2 to 30 carbon atoms; R3 is A-[CH2]m—B—[CH2]n—C—[CH2]p-D, wherein m, n and p are each independently zero or an integer from 1 to 12, and A, B, C and D are each independently selected from a covalent bond, amino, amido, oxygen, thio, carbonyl, carboxyl, oxycarbonyl, thiocarbonyl, phosphate, amino phosphate, mono-, di- and tri-amino phosphate group with the proviso that no two oxygen atoms are directly connected to each other; Z1 and Z2 are the same or different, each may be absent or independently selected from a) hydrogen, sodium, lithium, potassium, ammonium, mono-, di-, tri- and tetraalkylammonium, or b) together with the phospho group form a phospho ester of glycerol, choline, ethanolamine, inositol, serine, mono- or oligosaccharide.
WO03/000173 reports compounds of formula (I):
and pharmaceutically acceptable salts thereof, wherein R1 is a saturated or unsaturated chain of 1-18 carbons in length; and R2 is a saturated or unsaturated chain of 1-18 carbons in length, with the proviso that R1 and R2 are not both propyl; and compounds of formula (II):
and pharmaceutically acceptable salts thereof, wherein R1 is a saturated or unsaturated chain of 1-18 carbons in length; R2 is a saturated or unsaturated chain of 1-18 carbons in length; and A is selected from the group consisting of PO4—X, COOL and COHR′—R″, wherein X is a hydrogen or choline, L is a lipid moiety selected from the group consisting of glycerol, C3-20 fatty acid monoglycerides, C3-20 fatty acid diglycerides, hydroxy-C2-6-alkyl esters of C3-20 fatty acids, hydroxy-C2-6-alkyl esters of lysophosphatidic acids, lyso plasmalogens, lysophospholipids, lysophophatidic acid amides, glycerophosphoric acids, sphingolipids, lysophosphatidylethanolamine, and N-mono-(C1-4)alkyl and N,N-di-(C1-4)alkyl and quaternary derivatives of the amines thereof; and R′ and R″ are each independently selected from the group consisting of hydrogen and a lower alkyl group comprising 1-5 carbon atoms.